Stable aqueous formulation of 3-(N-butylacetamino)-propionic acid ethyl ester

ABSTRACT

The present invention relates to stable aqueous formulations of the insect repellent ethyl 3-(N-butyl-acetamino)propionate.

This application is a 371 of a PCT/EP97/05826, filed on Oct. 22, 1997.

The present invention relates to a stable aqueous formulation of thesubstance ethyl 3-(N-butyl-acetamino)propionate.

As is known, the substance ethyl 3-(N-butyl-acetamino)propionate has aninsect-repelling action and is also used in this role. The insectrepellent can be obtained commercially, for example from Merck KGaA,Darmstadt.

For people, insects are an annoyance or even a threat in a number ofrespects. As well as the damage caused by some types of insects (forexample the destruction of whole harvests), people and many animalsalike are annoyed, stung and otherwise troubled in one way or another bya large variety of insects. This can lead to infections and to thetransmission of dangerous diseases.

The main weapons in the fight against insects are insecticides, althoughtheir use and toxicity profile are not always without problems. Measuressuch as the use of insect eradicators are, however, not necessarilyrequired to prevent direct annoyance.

Since nowadays environmental protection is very much at the fore,preventive measures are preferably used.

Thus insect repellents are now likely to be preferred to insecticidesfor controlling insects, since the former are merely intended to preventinsects from settling on a host.

The requirements for an insect repellent are high and manifold. Aboveall, effective protection of the skin against insects must be ensured.Lasting repellency over a number of hours, even under climaticallyunfavourable conditions, is important. The repellent should have asbroad an activity spectrum as possible.

Other requirements are maximum skin and mucosa compatibility withouttoxic, allergenic or sensitizing properties, although there should be nopenetration of the skin.

In addition, the substance should have high chemical stability, i.e.should not undergo hydrolysis or (photo)oxidation, high thermalstability and high perspiration resistance.

Furthermore, an insect repellent must be readily compatible and misciblewith common cosmetic and pharmaceutical formulation bases.

The insect repellent ethyl 3-(N-butyl-acetamino)propionate satisfiesthis multiplicity of requirements.

It has however been established that this substance is degraded inaqueous formulations during the storage period. This degradation isspeeded up under the influence of elevated temperatures. Even atemperature increase of 10° C. can double the rate of degradation.

This must be considered a disadvantage, since it is often the case thatcorresponding insect repellent formulations are stored for years aftertheir manufacture and sale, or are only used now and again over a longperiod. In addition, higher temperatures (certainly 50° C. and above)are frequently encountered during the storage of cosmetic formulationsin summer, especially in southern countries. It is thus possible thatthe insect repellent will already have been so severely degraded thatits effect is considerably diminished.

It therefore appears desirable to provide aqueous or hydrousformulations of improved stability which have an unchanged content ofethyl 3-(N-butyl-acetamino)propionate over a long period, even atelevated temperatures.

Surprisingly, it has been found that the stability of aqueousformulations comprising ethyl 3-(N-butylacetamino)propionate can beconsiderably increased if formulations having a higher pH, preferablybuffered solutions, are used.

Base formulations for cosmetic or pharmaceutical preparations are oftenprepared on the basis of aqueous alcoholic solutions. Such formulationsare also known in connection with the insect repellent ethyl3-(N-butylacetamino)propionate. However, there are no indications at allin the literature that formulations having a higher pH, in particularbuffered formulations, are being used to improve stability.

The invention provides a stable aqueous formulation of the insectrepellent ethyl 3-(N-butylacetamino)propionate which is characterized inthat solutions having a higher pH, preferably buffered solutions, areused for stabilization.

The pH of these solutions is in a pH range greater than 3.0, preferablyin the range from 3.5 to 7.9. In addition to acids and bases, such as,for example, citric acid or sodium hydroxide solution, buffers can alsobe used for adjusting the pH.

Suitable buffer system include any known buffer solutions in this pHrange. Such buffers are generally known to the person skilled in the artand require no further explanation here.

According to the invention, a buffer selected from the following groupof buffer systems is preferred. This group of buffer systems is merelygiven by way of example and is in no way limiting with respect to theformulations according to the invention: citric acid/disodiumhydrogenphosphate, effective in a pH range from 2.2 to 7.8 (preferably0.1 M citric acid/0.2 M Na₂HPO₄), tris(hydroxymethyl)aminomethane/HCl,effective in the pH range around 7.2 to 9.0 (preferably 0.2 M/0.1 M),disodium citrate/HCl, effective in the pH range from 1.2 to 5.0(preferably 0.1 M/0.1 M), potassium hydrogenphthalate/NaOH, effective inthe pH range from 4.2 to 6.2 (preferably 0.1 M/0.1 M), disodiumcitrate/NaOH, effective in the pH range from 5.2 to 6.6 (preferably 0.1M/0.1 M), potassium dihydrogenphosphate/disodium hydrogenphosphate,effective in the pH range from 5.0 to 8.0 (preferably both 1/15 mol/l),or also triethanolamine+Titriplex III/HCl, effective in the pH rangefrom 7.0 to 8.8 (preferably 0.5 mol/l/0.05 mol/l).

The invention also provides for the use of solutions adjusted orbuffered using, for example, citric acid or sodium hydroxide solutionfor stabilizing hydrous formulations of the insect repellent ethyl3-(N-butylacetamino)propionate. The pH of these solutions is in therange greater than 3.0. The pH is preferably in the range from 3.5 to7.9.

Examples of suitable hydrous formulations are, inter alia, lotions,emulsions, like cream or milk (W/O or O/W), gels and also solid sticks.

In addition to other additives, UV filters can also be incorporated intothese hydrous formulations, giving sunscreens or UV-protectionformulations which can be applied to the skin and, if desired, also tothe hair. Examples of suitable UV filters obtainable commercially are,inter alia, Eusolex 6300®, Eusolex 4300®, Eusolex 9020®, Eusolex 232®,Eusolex 2292®, Eusolex OCR®, Eusolex HMS®, Eusolex 6007®, PABA andUvinul T 150®. UV filters can be incorporated individually or incombination with others into the formulations according to the inventionin concentrations of from 0.5 to 10% by weight.

An emulsion according to the invention in the form of an insectrepellent cream or milk can, in addition to the insect-repellingsubstance ethyl 3-(N-butylacetamino)propionate in solution or insolution with a suitable buffer, further comprise for example thefollowing substances: fatty alcohols, fatty acid esters, fatty acids,lanolin, natural or synthetic oils or waxes and emulsifiers in thepresence of water.

Lotions according to the invention comprise, inter alia, natural orsynthetic oils and waxes, lanolin, fatty acid esters, low molecularweight alcohols or polyols.

Most gels further comprise thickeners, such as, for example, silica.

The solid sticks consist of natural or synthetic waxes and oils, fattyalcohols, fatty acids, fatty acid esters and lanolin in addition to theadditives according to the invention.

The formulations according to the invention can also be in the form ofaerosols, in which case the usual propellants, such as alkanes,fluoroalkanes and fluorochloroalkanes, are used as a rule.

The composition and preparation of such hydrous formulations aregenerally known to the person skilled in the art and require no furtherexplanation here.

In another preferred embodiment, the pH in the formulations according tothe invention is in the range from 4.5 to 8.0, and a particularly strongstabilization effect is displayed by formulations having a pH between6.5 and 7.9.

The content of ethyl 3-(N-butylacetamino)-propionate in the formulationsaccording to the invention is 1 to 50% by weight, preferably 10 to 30%by weight.

The formulations according to the invention are prepared simply bymixing the individual components with stirring.

The provision of the formulations according to the invention makesavailable aqueous or hydrous formulations of ethyl3-(N-butylacetamino)propionate which have an unchanged content of thissubstance over a long period. Even at high storage temperatures of from30° to above 40° C. there is practically no decomposition with thepreferred higher pH values.

Even without further elaboration, it is assumed that a person skilled inthe art can utilize the above description to the full extent. Thepreferred embodiments are therefore merely to be seen as a descriptivedisclosure which is in no way limiting.

The complete disclosure contents of all applications, patents andpublications cited above and below are incorporated herein by reference.

For clarification and illustration, examples are given below which arewithin the scope of the present invention, but which are not intended tolimit the invention to these examples.

EXAMPLE 1

Using the buffer system 0.1 M citric acid/0.2 M sodium sulfate,solutions of pH 3.5, 4.4 and 6.5 are prepared by simply mixing thecomponents with stirring. This buffer system can thus be effective overa broad pH range.

a) A solution of pH 3.5 having the following composition (in % by wt.)is prepared:

Ethyl 3 - (N-butylacetamino)propionate (1) 10.0% (Art. No. 111887) 96%ethanol (Art No. 100971) (1) 15.0% Buffer pH 3.0 ad 100.0%

b) A solution of pH 4.4 having the following composition (in % by wt.)is prepared:

Ethyl 3 - (N-butylacetamino)propionate (1) 10.0% (Art. No. 111887) 96%ethanol (Art No. 100971) (1) 15.0% Buffer pH 4.0 ad 100.0%

c) A solution of pH 6.5 having the following composition (in % by wt.)is prepared:

Ethyl 3 - (N-butylacetamino)propionate (1) 10.0% (Art. No. 111887) 96%ethanol (Art No. 100971) (1) 15.0 Buffer pH 6.0 ad 100.0% Source ofsupply: (1) Merck KGaA, Darmstadt

EXAMPLE 2

Using the buffer system 0.2 M tris(hydroxymethyl)aminomethane/0.1 M HCl,a solution of pH 7.9 is prepared by mixing the following components withstirring (amounts in % by wt.)

Ethyl 3 - (N-butylacetamino)propionate (1) 10.0% (Art. No. 111887) 96%ethanol (Art No. 100971) (1) 15.0% Buffer pH 8.0 ad 100.0% Source ofsupply: (1) Merck KGaA, Darmstadt

Example A

The stability of ethyl 3-(N-butylacetamino)-propionate was tested inbuffered solutions as a function of pH. The aqueous formulationsaccording to the invention, prepared as in Examples 1 and 2, weresubjected to a storage test over 12 months both at room temperature andat 40° C.

The results are given in Tables 1 and 2.

TABLE 1 pH of Storage at room the temperature [months] buffered 0 3 6 912 solution repellent content in % 3.5 10.1 8.8 8.0 7.2 6.4 4.5 10.2 9.89.6 9.4 9.0 6.5 10 2 9 8 9.7 9.6 9 3 7.9 10.2 9.7 9.6 9.7 9.5

TABLE 2 pH of Storage at room the temperature [months] buffered 0 3 6 912 solution repellent content in % 3.5 10.1 5.8 3.5 2.8 2.7 4.5 10.2 8.27.0 5.3 4.0 6.5 10.2 9.3 8.5 7.8 6.8 7.9 10.2 9.6 9.3 8.9 7.9

Example B

In this example, aqueous solutions of ethyl3-(N-butylacetamino)propionate were subjected to a storage test at 40°C. as a function of pH. The corresponding aqueous solutions comprise thefollowing:

Solution 1 (pH 4.5):

in % by wt. Ethyl 3 - (N-butylacetamino)propionate 10.0 (Art. No.111887) (1) 96% ethanol (Art No. 100971) (1) 15.0 NaCl (Art. No. 6400)(1) 0.1 Water, demin. ad 100.0 pH adjustment with hydrochloric acid

Solution 2 (pH 6):

Composition as for solution 1; pH adjustment to pH 6 with sodiumhydroxide solution.

Solution 3 (pH 8):

Composition as for solution 1; pH adjustment to pH 8 with sodiumhydroxide solution. Source of supply: Merck KGaA, Darmstadt

The results of the storage test of the different solutions aresummarized in Table 3.

TABLE 3 pH of Storage at room the temperature [months] buffered 0 3 6 912 solution repellent content in % (1) 4.5  9.9 4.4 2.7 2.2 2.5 (2) 6.010.1 6.0 2.9 2.5 2.6 (3) 8.0 10.0 8.6 3.0 2.5 2.6

A comparison of Tables 2 and 3 clearly shows that the insect repellentin the buffered formulations according to the invention is considerablymore stable, and degradation is markedly slowed, in particular at higherpHs.

What is claimed is:
 1. A stable aqueous formulation of the insectrepellent ethyl 3-(N-butylacetamino) propionate, comprising ethyl3-(N-butylacetamino) propionate in a buffered solution or buffer systemhaving a pH of 3.5 or greater, selected from a group consisting ofcitric acid/Na₂HPO₄, tris(hydroxymethyl) amino-methane/HCl, disodiumcitrate/HCl, potassium hydrogen-phthalate/NaOH, disodium citrate/NaOH,potassium dihydrogenphosphate/disodium hydrogenphosphate, andtriethanolamine and Titriplex III/HCl.
 2. The formulation according toclaim 1, wherein the pH is in a range of pH 3.5-7.9.
 3. The formulationaccording to claim 1, wherein the insect repellent is in a concentrationof 1% by weight-50% by weight.
 4. The formulation according to claim 3,wherein the concentration of insect repellent is 10-30% by weight. 5.The aqueous formulation according to claim 1, further comprising one ormore UV filters in a concentration of 0.5-10% by weight.
 6. The aqueousformulation according to claim 1 in the form of a lotion, emulsion,cream or milk, gel or solid stick.
 7. The formulation of claim 1,wherein the pH is 4.5 or greater.
 8. A method of repelling insects,comprising applying to a subject a stable aqueous formulation of aninsect repellent containing ethyl 3-(N-butylacetamino) propionate, whichis buffered at a pH at least 3.5 by a buffer system, wherein said buffersystem is citric acid/Na₂HPO₄, tris(hydroxymethyl) aminomethane/HCl,disodium citrate/HCl, potassium hydrogenphosphate or triethanolamine andTitriplex III/HCl.
 9. The method according to claim 8, wherein the pH ofthe solution is pH 3.5-7.9.
 10. The method according to claim 8, whereinthe insect repellent is in a concentration of 1% by weight-50% byweight.
 11. The method of claim 10, wherein the concentration of insectrepellent is 10-30% by weight.